The scaled particle theory for mixtures of hard spheres has been applied to determine the desolubilizing effect of non-binding proteins of arbitrary size upon the solubility of Hb S. This methodology successfully accounts for the observed solubility behavior of Hb S in mixtures with other hemoglogin species. We have found that the relatively nontoxic chemical hexamethylenetetramine retards the kinetics of polymerization and increases the solubility of HbS to a greater extent than any noncovalent inhibitor of gelation at comparable concentrations. These effects arise from the slight decomposition of HMT at neutral pH to form HCHO which cross-links the hemoglobin. We have shown that is possible to cross-link hemoglobin within red cells and that this effect is enhanced in the presence of reducing agents such as ascorbic acid. Preliminary experiments to effect intracellular cross-linking of hemoglobin in vivo, in dogs, have not been successful.